Carcinogenicity of lipid-lowering drugs

Summary

This article has created considerable concern among the public about the
safety of cholesterol-lowering medication. The authors report on carcinogenicity
data culled from the Physician's Desk Reference and then argue against
drug therapy of hyperlipidemia in the primary prevention of coronary disease.
The authors' points are rebutted in an accompanying editorial.

Carcinogenicity data

The authors summarize animal carcinogenicity data for lipid-lowering
drugs, obtained from the 1994 PDR. These data are then compared to data
for commonly used antihypertensive medications. The method for comparing
animal doses to human doses was changed for lovastatin and gemfibrozil
in 1993: prior to that year, the doses were compared on an administered,
mg/kg basis; thereafter blood-levels achieved (area under the curve) were
compared. Since the small animals used in the studies metabolize these
drugs more quickly than humans, much higher doses are required in the animals
to achieve comparable blood-levels.

The results are given in a table, which reveals that the fibric acid
derivatives and the statins cause a number of different malignancies and
benign tumors (in particular liver, thyroid and Leydig cell) in rats and
mice, at blood levels that are often comparable to those seen with human
dosing regimens. No studies were cited for niacin; cholestyramine was found
to enhance intestinal carcinogenesis only in the presence of other carcinogenic
factors.

Another table presents similar data for a number of commonly used antihypertensive
agents, such as ACE inhibitors, beta-blockers, calcium channel blockers
and diuretics. For 41 drugs for which results were reported, only 32% were
found to be carcinogenic (15% malignant, 17% benign).

Authors' Discussion

The authors note that carcinogenicity in laboratory animals cannot be
directly extrapolated to humans, particularly if an established mutagenic
mechanism has not been found (as in the drugs examined here). They argue,
however, that the evidence for cancer-causation in rats and mice is worrisome,
and that the exposures that cause tumors in animals, when expressed as
blood-level areas under the curve are comparable to blood-levels achieved
in humans on therapeutic doses.

In terms of the individual drugs, the authors are most critical of the
fibrates (gemfibrozil), because of a higher total mortality in two large
studies. For the statins, they note that there was no increase in cancer
deaths after 5.4 years of follow-up in the Scandinavian Simvastatin Survival
Study, but express concern that the latency period for the development
of cancer could be 10 years or longer. They express much less concern about
niacin and the resins.

Beyond the data presented here, the authors make a number of points
that they have made in the past, in other articles. They reaffirm the role
of lipid-lowering therapy in the secondary prevention of coronary
disease (hyperlipidemic patients with documented atherosclerotic disease,
at high risk of coronary events). They suggest that, for primary prevention,
where the short-term risk of coronary events is low, meta-analyses of trials
suggest that the overall risk of cholesterol lowering may exceed the benefits.
They note that meta-analyses of trials looking specifically at cancer deaths
found no significant increase when follow-up was extended, but caution
that medications may not have been continued for extended periods in these
trials.

Editorial

Authors: Dalen J, Dalton W
Source: JAMA. 275:67-9.

In an accompanying editorial, Dalen and Dalton rebut the points made
by Newman and Hulley.

They argue that the rodent carcinogenicity data is flawed: the rats
used have a high spontaneous cancer rate, and 50% of chemicals tested in
these animals will be identified as carcinogens. Although cancer was produced
in the animals at blood levels similar to those obtained with therapy in
humans, in order to achieve these levels, much higher mg/kg doses had to
be administered to the animals (because of rapid metabolism). Such high
oral doses can lead to very high tissue exposure in the liver and GI tract,
causing non-specific damage and possibly neoplasia on that basis. In fact,
many of the tumors noted in the animals were in the GI tract and liver.

Turning to the analysis of clinical trial data, the authors point out
that one of three meta-analyses found no increase in cancer deaths, the
other two analyses found only a very small excess cancer death rate in
the treatment groups (0.002-0.003), and that these were accounted for by
two trials, a clofibrate and a dietary trial. Looking at the late follow-up
data from several large trials, there is also no evidence of increased
cancer incidence here.

Dalen and Dalton conclude that primary prevention of coronary disease
by pharmacological treatment of hyperlipidemia should not be questioned
based on the data presented here, although the appropriate age to begin
screening is not yet clear and has important cost-benefit implications.

Comment

The article by Newman and Hulley was picked up by the media, and has caused
quite a bit of anxiety so far. In my opinion, a few points need to be emphasized:

Even Hulley and Newman, who represent a fairly extreme position in the
spectrum of approaches to hypercholesterolemia, do not dispute the use
of cholesterol lowering therapy in secondary prevention.

The data presented in their article is not new data, only an analysis of
data from the Physicians' Desk Reference.

Their strongest criticism is reserved for the use of the fibrates (gemfibrozil),
for which the evidence of lowering mortality is, in fact, weakest among
the lipid-lowering agents.

In a recently completed trial (the West of Scotland trial), one of the
statins was, in fact, found to decrease all-cause mortality when used as
a primary prevention strategy.

1/9/96

Reader comments

I would have far preferred to see their article listed as an opinion
piece or editorial-type format, rather than as an original article. It
did cause a lot of distress to my patients and the news reports were very
misleading. Although I feel strongly that journals should print other than
"mainstream" views, it's important to realize that publication is assumed
by the public to mean "truth" and "endorsement."